The growth and survival of neoplastic cells is regulated by both internal genetic control within the tumor cells and by host factors. In a very small population of cancer patients, progression of malignant tumors can be partially or completely reversed via an unknown host mechanism termed "spontaneous regression." Lack of animal models for spontaneous regression has hampered the efforts to identify the factors involved in this efficient mechanism of tumor resistance. Dr. Cui and his colleagues have identified, through unexpected observations, a unique mouse mutation conferring the spontaneous regression of late-stage ascites induced by the transplantation of very aggressive mouse sarcoma 180 cells. The spontaneous regression of late-stage ascites is complete and permanent in the mice carrying the mutation. This mutation also protects the mice against tumor development following transplantation of mouse leukemia cells. This mutation segregates as a dominant trait consistent with a single locus. Initial genotype analysis established a linkage of this mutation to two adjacent microsatellite markers on mouse chromosome 4. In this proposal Dr. Cui has assembled a group of experts from genomics, pathology, immunology, carcinogenesis and biochemistry to determine the genetic basis, cellular mechanism and anti-tumor spectrum of this powerful tumor resistance trait. The long-term objective of this proposal is to determine if a similar mechanism can be also effective in human cancer treatment and prevention. This proposal has 5 specific aims: 1) to establish a high-resolution genetic linkage map for the critical region of the mutation on chromosome 4 by genotyping analysis; 2) to construct a physical map for this critical region; 3) to evaluate the candidate genes in the critical region by DNA; 4) to determine the cellular mechanism by which the progression of tumors is reversed and 5) to determine if the mutation offers protection against carcinogen-induced endogenous epithelial tumors. Completion of these aims will provide a comprehensive understanding of the biological mechanism of this unique, powerful resistance to tumors. Necessary tools will be developed to extend these studies to search for similar genes in humans and to design better, more efficient strategies of cancer treatment and prevention.